The present invention relates generally to a non-human host model for human tumors. More particularly, this invention relates to a hon-human host model implanted with a human tumor obtained from a human host and utilized for assessing the chemosensitivity of the implanted human tumor to an anti-tumor agent.
The lack of clinically relevant tumor models of different human cancers is a major obstacle in the development of new and effective treatments for cancer especially for treatment of individual patients. Although heterotransplants of certain human tumors have been successfully grown in non-human host subjects such as nude mice, such heterotransplants have never been appropriately been explored for prediction of in vivo chemosensitivity to anti-tumor agents.
Most potential anti-tumor agents discovered and tested in clinical trials are rarely approved for use in treatment of cancer. Typically, the majority of the potential anti-tumor agents tested are abandoned for lack of anti-tumor activity during Phase II clinical studies rather than intolerable and/or unpredictable toxicity. Some of the current in vitro anti-tumor agent screening systems utilized by the National Institute of Health and the pharmaceutical industry involve the use of human tumor cell lines derived from multiple sequential in vitro subcultures generated from human tumor explants. Such cell lines are well characterized from a molecular standpoint and are useful in identifying molecular determinants of in vitro sensitivity and/or confirming putative molecular mechanisms of action for the compounds of the anti-tumor agents being screened. Such screening systems have limited usefulness because most human tumors comprise accumulated genetic and molecular abnormalities which produces a high degree of phenotypic heterogeneity. Thus, the relevance of such screening systems for predicting in vivo clinical activity remains to be established.
New anti-tumor agents are routinely screened in vivo using human tumor xenografts which are grown subcutaneously in non-human host subjects such as nude mice. Typically, clinical trials of new anti-tumor agents measure tumor growth inhibition rather than tumor shrinkage as an indicator of anti-tumor activity. Such xenografts do not exhibit the heterogenous population of tumor cells which are representative of the human tumor from which they are derived. Furthermore, the vascularity and stroma of such xenografts are exclusively of murine origin. Generally, such xenografts have been selected to suit the putative molecular mechanism of the anti-tumor agent tested. This approach focuses on the proof of principle as to the in vivo model rather than accessing or screening the anti-tumor agent using a panel of clinically relevant and predictive models. If panels of in vivo experimental tumor models clinically representative of each major human cancer type were available, the selection criteria for pursuing the clinical development of novel anti-tumor agents would be stricter but the likelihood of identifying useful anti-tumor agents for particular tumors would be much higher. These would reduce the cost and patient resources required for anti-tumor agent development.
Similarly, if individualized models of human cancer were developed, such models would facilitate the process of selecting the optimal therapy for a particular patient""s tumor. In vitro sensitivity tests using tumor cells derived from fresh tumor specimens have been known and used extensively. Such tests are typically more useful in confirming a tumor""s resistance to anti-tumor agents which have been previously known to show little activity against a particular tumor rather than selecting the most active anti-tumor agent. In addition, in vitro assay systems can not account for the in vivo pharmacological determinants of anti-tumor activity.
The present invention is generally directed to a method of evaluating the chemosensitivity of a tumor to an anti-tumor agent in vivo. The method comprises generally of extracting a portion of a tumor from a human host and inserting it into a non-human host subject such as a nude immunodeficient mouse. The implanted tumor is permitted to grow to a minumum preseslected size to form a test tumor. Once the tumor reaches the prerequisite size, an amount of an anti-tumor agent is administered to the non-human host subject sufficient to determine whether the anti-tumor agent is effective in treating the test tumor. The test tumor is then examined to determine the anti-tumor activity of the anti-tumor agent. The present invention is also directed to a method of treating a patient suffering from the presence of a tumor is also contemplated.
In particular, one aspect of the present invention is directed to a method of evaluating the chemosensitivity of a tumor to an anti-tumor agent in vivo, comprising:
a) extracting a portion of a tumor from a human host;
b) inserting the portion of the tumor into a first non-human host subject;
c) growing the tumor portion in the first non-human host subject to a minimum preselected size to form a test tumor;
d) administering an amount of an anti-tumor agent into the first non-human host subject sufficient to determine whether the anti-tumor agent is effective in treating the test tumor; and
e) assessing the anti-tumor activity of the anti-tumor agent on the test tumor.
Another aspect of the present invention is directed to a method of treating a patient suffering from the presence of a tumor, comprising:
a) extracting at least one portion of the tumor from the patient;
b) inserting the portion of the tumor into a first non-human host subject;
c) growing the tumor portion in the first non-human host subject to a preselected minimum size to form a test tumor;
d) administering an amount of an anti-tumor agent into the first non-human host subject sufficient to determine whether the anti-tumor agent is effective in treating the test tumor;
e) assessing the anti-tumor activity of the anti-tumor agent; and, if positive
f) administering an effective amount of the anti-tumor agent to said patient.